CUX1 regulates human hematopoietic stem cell chromatin accessibility via the BAF complex

Liu, Weihan; Kurkewich, Jeffrey L.; Stoddart, Angela; Khan, Saira; Anandan, Dhivyaa; Gaubil, Alexandre N.; Wolfgeher, Donald J.; Jueng, Lia; Kron, Stephen J.; McNerney, Megan E.

doi:10.6082/xsbmw-1d910

Published May 11, 2024 | Version v1

Journal article Open

CUX1 regulates human hematopoietic stem cell chromatin accessibility via the BAF complex

1. University of Chicago

CUX1 is a homeodomain-containing transcription factor that is essential for the development and differentiation of multiple tissues. CUX1 is recurrently mutated or deleted in cancer, particularly in myeloid malignancies. However, the mechanism by which CUX1 regulates gene expression and differentiation remains poorly understood, creating a barrier to understanding the tumor-suppressive functions of CUX1. Here, we demonstrate that CUX1 directs the BAF chromatin remodeling complex to DNA to increase chromatin accessibility in hematopoietic cells. CUX1 preferentially regulates lineage-specific enhancers, and CUX1 target genes are predictive of cell fate in vivo. These data indicate that CUX1 regulates hematopoietic lineage commitment and homeostasis via pioneer factor activity, and CUX1 deficiency disrupts these processes in stem and progenitor cells, facilitating transformation.

Data availability

The mass spectrometry proteomic datasets (MMSK1, MMSK2) were uploaded to the ProteomeXchange consortium via the PRIDE partner repository with the dataset identifier PRIDE:PXD037838. ChIP-seq, CUT&RUN and ATAC-seq data are available at NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GEO:GSE235309. The data will be publically accessible by the paper's publishment date.

The code for machine learning cell fate prediction (Figure 4E) can be accessed on Github (https://github.com/AlexandreGaubil/mcnerney-cux1-ML). The code used for Hi-C integration analysis (Figure 4A) can be accessed on Github (https://github.com/liuweihanty/CD34_HiC_CUX1_integration)

Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

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